Dose Optimization and Expansion Study of DFV890 in Adult Patients With Myeloid Diseases

NCT05552469 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: CDFV890G121012022-501406-36-00
• Study Type: interventional
• Target: 62
• Locations: 8 countries
• Sites: 26

Brief Summary

Study CDFV890G12101 is an open-label, phase 1b, multicenter study with a randomized two-dose optimization part, and a dose expansion part consisting of three groups evaluating DFV890 in patients with myeloid diseases. The purpose of this study is to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy and recommended dose for single agent DFV890 in patients with lower risk (LR: very low, low or intermediate risk) myelodysplastic syndromes (LR MDS), lower risk chronic myelomonocytic leukemia (LR CMML) and High-Risk Clonal Cytopenia of Undetermined Significance (HR CCUS).

Conditions

Myeloid Diseases

Keywords

MDS; CMML; CCUS; CHRS; NLRP3; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; inflammasome; CYP2C9

Outcome Measures

Primary Outcomes (3)

• Incidence of Dose-limiting Toxicities (DLTs)

  A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as clinically relevant, occurring during the DLT monitoring period following the first administration of study treatment.

  28 days

• Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs) and laboratory values qualifying and reported as AEs.

  36 months

• Incidence of dose interruptions, discontinuations and reductions

  Number of patients with dose adjustments (interruptions, discontinuations and reductions) summarized by treatment group.

  36 months

Secondary Outcomes (18)

• Reduction in red blood cell (RBC) / platelet transfusions from baseline for transfusion-dependent (TD) patients

  Baseline, 36 months

• Percentage of patients developing transfusion independence (TI) for ≥8 weeks, ≥12 weeks, ≥16 weeks or ≥24 weeks for TD patients

  Baseline, 8 weeks, 12 weeks, 16 weeks and 24 weeks

• Best overall response (BOR) per 2006 IWG criteria for MDS and CMML

  Baseline, 36 months

• Hematological improvement per 2006 IWG criteria for MDS and CMML.

  36 months

• Rate of hematological improvement per 2006 IWG criteria for CCUS

  36 months

Study Arms (3)

Dose escalation: DFV890 low dose

EXPERIMENTAL

DFV890 given as single agent at a low dose

Drug: DFV890

Dose escalation: DFV890 high dose

EXPERIMENTAL

DFV890 given as single agent at a high dose

Drug: DFV890

Dose expansion: DFV890 low dose

EXPERIMENTAL

DFV890 given as single agent at a low dose

Drug: DFV890

Interventions

DFV890 DRUG

DFV890 Single Agent

Dose escalation: DFV890 high dose; Dose escalation: DFV890 low dose; Dose expansion: DFV890 low dose

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF) 2. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 3. Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions guidelines and must be willing to undergo a bone marrow aspirate.
• \. Patients must have one of the following for eligibility into the study:
• In dose optimization: IPSS-R defined very low, low or intermediate risk Myelodysplastic Syndrome (LR MDS) who failed to respond to or did not tolerate ESAs or luspatercept or HMAs and patients with del 5q who failed to respond to or did not tolerate lenalidomide; or
• In dose optimization and expansion: IPSS-R defined very low, low or intermediate risk Chronic Myelomonocytic Leukemia (LR CMML) who failed to respond to or did not tolerate hydroxyurea or HMAs.
• changes for dose expansion (applicable as of amendment 3):
• LR MDS with ≤ 10% bone marrow blasts, IPSS-R score of ≤ 3.5, transfusion independent (TID) status as per IWG 2006 criteria (requiring \<4U pRBC in 8 weeks), clinically meaningful cytopenia(s) and no or limited (\<4 months) prior therapy for MDS.
• LR CMML patients with symptomatic cytopenias and/or constitutional symptoms refractory, intolerant or unsuitable for standard first-line therapy.
• HR-CCUS: Diagnosis of high-risk CCUS by clonal hematopoiesis risk score (CHRS) with clinically meaningful cytopenias and no prior therapy for a myeloid neoplasm.

You may not qualify if:

• \. Systemic antineoplastic therapy (including cytotoxic chemotherapy, alpha-interferon, kinase inhibitors or other targeted small molecules, and toxin-immunoconjugates) or any experimental therapy within 28 days or 5 half-lives, whichever is longer, and recovered from the toxicities before the first dose of study treatment. For patients that received antibodies the washout period is 4 weeks prior to study treatment.
• a. For TID LR MDS in Dose Expansion Phase only (applicable as of amendment 03):
• Prior therapy for MDS administered for \>4 months (ESA and luspatercept administered for ≤4 months will be allowed if washout period followed)
• Concurrent malignancy requiring active systemic therapy
• Prior or concurrent cytotoxic chemotherapy for MDS at any time
• \. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
• \. Patients who have previously been treated with agents that have the same mechanism of action as DFV890 as defined in Table 6-7, list of prohibited medications (e.g., drugs targeting the NLRP3 inflammasome pathway and the IL-1 pathway (canakinumab and anakinra)).
• \. Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents anytime ≤ 1 week (or 5 half lives, whichever is longer) prior to start of study treatment.
• \. Patients receiving:
• a. concomitant medications that are known to be modulators of cytochrome P450 enzymes CYP2C9 and/or CYP3A (specifically strong or moderate inducers of CYP2C9, strong inducers of CYP3A enzymes, strong inhibitors of CYP2C9 and/or strong or moderate dual inhibitors of CYP2C9/CYP3A); and b. patients, who are poor CYP2C9 metabolizers receiving concomitant medications known to be strong or moderate inhibitors of CYP3A, whose concomitant medications cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to start of study treatment and for duration of the study. See Section 6.8 and list of prohibited drugs in Appendix 8 for more details.
• \. Dose expansion only: Poor CYP2C9 metabolizers defined as genotype of the CYP2C9 \*3/\*3 or CYP2C9 \*2/\*3 allele combinations are excluded.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (26)

Stanford Cancer Center

Stanford, California, 94305, United States

Location

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Sidney Kimmel CCC At JH

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

Weill Cornell Medicine NY-Presb

New York, New York, 10021, United States

Location

Memorial Sloan Kettering Cancer Ctr

New York, New York, 10065, United States

Location

Vanderbilt University Medical Ctr

Nashville, Tennessee, 37232, United States

Location

Univ of TX MD Anderson Cancer Cntr

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Novartis Investigative Site

Grenoble, 38043, France

Location

Novartis Investigative Site

Nantes, 44093, France

Location

Novartis Investigative Site

Paris, 75475, France

Location

Novartis Investigative Site

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Novartis Investigative Site

Dresden, Saxony, 01307, Germany

Location

Novartis Investigative Site

Leipzig, Saxony, 04103, Germany

Location

Novartis Investigative Site

Lübeck, 23538, Germany

Location

Novartis Investigative Site

Hong Kong, 999999, Hong Kong

Location

Novartis Investigative Site

Brescia, BS, 25123, Italy

Location

Novartis Investigative Site

Rozzano, MI, 20089, Italy

Location

Novartis Investigative Site

Singapore, 119074, Singapore

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Cardiff, CF14 4XW, United Kingdom

Location

Novartis Investigative Site

London, SE5 9RS, United Kingdom

Location

Novartis Investigative Site

Manchester, M20 2BX, United Kingdom

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2022
• First Posted: September 23, 2022
• Study Start: May 8, 2023
• Primary Completion (Estimated): January 13, 2027
• Study Completion (Estimated): January 13, 2027
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

DE (4); SG (1); IT (2); GB (3); ES (1); HK (1); FR (3); US (11)